PROJECT SUMMARY/ABSTRACT Abnormal accumulation of amyloid ? (A?) peptide into oligomers and larger aggregates is hypothesized to initiate a pathogenic cascade leading to Alzheimer?s disease (AD). Given the critical role of A? in AD pathogenesis, strategies to modulate A? production and clearance are actively being pursued as AD therapies. Toward that end, we seek to define the role of microRNAs (miRNAs), specifically miR-758, in AD pathogenesis. Mounting evidence strongly suggests that miRNA dysregulation may contribute to neurodegenerative disorders, including AD. We recently found that A? induces brain-enriched miR-758 expression and miR-758 increases A? levels. In this application, we propose to investigate the role of miR- 758 in cognition and Alzheimer?s disease by using primary neuronal cells (Aim 1) and an APP/PS1 transgenic mouse model (Aim 2). We will determine whether overexpression of miR-758 impairs learning and memory and trigger neuronal cell death in an APP/presenilin mouse model by increasing toxic A? accumulation in brain. If so, this mouse line will be a valuable model system to test neuroprotective therapeutics in vivo, overcoming the lack of overt cell death in almost all APP mouse models.